HGG-12. HYPOXIA SEEMS TO BE FREQUENTLY UPREGULATED IN THE PEDIATRIC HIGH GRADE GLIOMA AND DIPG

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2017-06, Vol.19 (suppl_4), p.iv25-iv25
• Main Authors: Blandin, Anne-Florence, Durand, Aurelie, Litzler, Marie, Guerin, Eric, Jacques Namer, Izzie, Guenot, Dominique, Entz-Werle, Natacha
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nox083.101

Pediatric high grade glioma (pHGGs), including sus-tentorial and DIPG, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. We, previously, observed that the resistance to mTor and HIF1 inhibitions was completely linked to HIF2 hyperexpression spontaneously in the pHGG and DIPG cell lines. To establish, the crucial role of the hypoxic pathways in pHGG tumors themselves, we assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs, as well as the metabolomic status. We tested 28 patients and could isolate 4 types of tumor profiles with immunohistochemical analyses. The first one was defined by the absence of HIF/HIF2 expression (6 tumors), the second one was just overexpressing HIF1 (9 tumors), the third one is the smaller with an isolated HIF2 hyperexpression (3 cases) and the last one where HIF1 and HIF2 and concomitantly expressed. The DIPG subgroup was statistically associated with HIF2 hyperexpression and the complete absence of mTor expression. At the transcriptomic level, most of the tumors were overexpressing constantly and mainly RAS, HIF1, RPS6KB1, VHL, ENG and VEGFA, whereas mTOR, AKT, CXCL12 and CXCR4 were modulated throughout the tumors’ cohort. The metabolomic profiles showed a constant activated glycolysis in all tumors, whereas glutaminolysis and seronolysis were heterogeneously present. The only significant association was the presence of the lipolytic pathways and HIF2 hyperexpression, as already linked in our previous work. The combination of new drugs targeting hypoxia biomarkers and metabolic pathways like glycolysis and/or lipolysis might be a new approach in pHGG and DIPG.